Continuous synthesis process and device of prothioconazole intermediate

Abstract

The invention relates to the technical field of pesticides, in particular to a continuous synthesis process and device for a prothioconazole intermediate, and the continuous synthesis process at least comprises the following steps: synthesizing hydrazone from a BL-6 oil phase and formaldehyde in a continuous formation hydrazone reactor; synthesizing a BL-7 mixed phase from hydrazone, a thiocyanate aqueous solution and a dilute acid aqueous solution in a continuous ring-closing static tubular reactor; carrying out phase separation on the BL-7 mixed phase in a continuous phase separation reactor to obtain a BL-7 oil phase and a salt water phase; and the BL-7 oil phase is directly subjected to synthesis of prothioconazole without desolvation. Precise preparation of the key intermediate BL-7 is achieved through the modular continuous flow reaction system, compared with a traditional kettle type process, the continuous production period is shortened to 1 / 6 of that of an original process, the raw material utilization rate is increased by 20%, the three-waste generation amount is reduced by 50%, the risk of enrichment of highly toxic substances such as thiocyanic acid in the traditional process is effectively avoided, and the modular continuous flow reaction system is more suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pesticides, in particular to a continuous synthesis process and device for an intermediate of prothioconazole. BACKGROUND

[0002] The chemical name of prothioconazole is (RS)-2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-2,4-dihydro-1,2,4-triazole-3-thione, which is mainly used for preventing and treating many diseases of cereal, wheat and legume crops, etc. The efficient and green synthesis of the key intermediate to a certain extent determines the production efficiency and quality of prothioconazole technical material. The synthesis yield of 2-(1-chloro-cycloprop-1-yl)-1-(2-chlorophenyl)-2-hydroxy-3-(1,2,4-triazolidin-5-thione-1-yl)-propane (hereinafter referred to as BL-7) is low, the reaction repeatability is poor, a large amount of inorganic salt waste solid is produced, the post-treatment operation of the reaction is complex, which causes great pressure on economy and environment, and greatly restricts the industrialized large-scale production of prothioconazole technical material. A preparation method of a prothioconazole intermediate is disclosed in Chinese patent (authorized publication number CN107445909B), which mainly improves the synthesis yield and reduces solid waste by using dropwise addition of formaldehyde aqueous solution in toluene and optimizing the reaction conditions of subsequent and thiocyanate, but the production cycle is long, the safety risk is large, the equipment requirement is high, and it is not easy for industrialized large-scale production. SUMMARY

[0003] In order to solve the above problems, the present application provides a continuous synthesis process for a prothioconazole intermediate, which realizes the precise preparation of the key intermediate BL-7 through a modular continuous flow reaction system. Compared with the traditional kettle process, the continuous production cycle is shortened to 1 / 6 of the original process, the raw material utilization rate is increased by 20%, and the amount of three wastes is reduced by 50%, which effectively avoids the enrichment risk of toxic substances such as thiocyanic acid in the traditional process, and is more suitable for industrial production.

[0004] In one aspect, the present application provides a continuous synthesis process for a prothioconazole intermediate, which at least includes the following steps: synthesizing a hydrazone in a continuous hydrazone reactor by using BL-6 ([1-(2-chlorophenyl)-2-(1-chlorocyclopropyl)-2-hydroxy]-propylhydrazine) oil phase and formaldehyde; synthesizing BL-7 mixed phase in a continuous ring-closing static tubular reactor by using the hydrazone, thiocyanate aqueous solution and dilute acid aqueous solution; and obtaining BL-7 oil phase and salt water phase in a continuous phase separation reactor by using the BL-7 mixed phase, wherein the BL-7 oil phase contains a prothioconazole intermediate BL-7. The BL-7 oil phase does not need to be desolventized and can be directly used for the synthesis of prothioconazole.

[0005] In one embodiment, the BL-6 oil phase includes BL-6 and a solvent, and the weight ratio of the BL-6 and the solvent is 1: (1-20).

[0006] In one embodiment, the weight ratio of the BL-6 and the solvent is 1: (2~10).

[0007] In one embodiment, the weight ratio of the BL-6 and the solvent is 1: (3~5).

[0008] In one embodiment, the solvent is selected from one or more of toluene, xylene, dichloroethane, trichloroethane, dichloromethane, ethyl acetate or cyclohexane.

[0009] In one embodiment, the formaldehyde is selected from one or more of gaseous formaldehyde, 5~40wt% formaldehyde aqueous solution or paraformaldehyde.

[0010] In one embodiment, the formaldehyde is 30-35wt% formaldehyde aqueous solution.

[0011] In one embodiment, the weight ratio of the thiocyanate and water in the thiocyanate aqueous solution is 1: (1~5).

[0012] In one embodiment, the weight ratio of the thiocyanate and water in the thiocyanate aqueous solution is 1: (2~3).

[0013] In one embodiment, the thiocyanate is selected from one or more of potassium thiocyanate, sodium thiocyanate, ammonium thiocyanate, mercury thiocyanate or lead thiocyanate.

[0014] In one embodiment, the weight ratio of the acid and water in the dilute acid aqueous solution is 1: (1~5).

[0015] In one embodiment, the weight ratio of the acid and water in the dilute acid aqueous solution is 1: (2~3).

[0016] In one embodiment, the acid is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, carbonic acid or sulfurous acid.

[0017] In one embodiment, the molar ratio of the BL-6 and the formaldehyde is 1: (1.0~2).

[0018] In one embodiment, the molar ratio of the BL-6 and the formaldehyde is 1: (1.1~1.2).

[0019] In one embodiment, the molar ratio of the BL-6 and the thiocyanate is 1: (1~3).

[0020] In one embodiment, the molar ratio of the BL-6 and the thiocyanate is 1: (1.1~1.2).

[0021] In one embodiment, the molar ratio of BL-6 to acid is 1: (0.6-1.1).

[0022] In one embodiment, the molar ratio of BL-6 to acid is 1: (0.7-0.8).

[0023] In one embodiment, the temperature in the continuous hydrazone formation reactor is -25-25°C.

[0024] In one embodiment, the temperature in the continuous hydrazone formation reactor is -10-10°C.

[0025] In one embodiment, the temperature in the continuous hydrazone formation reactor is -5-5°C.

[0026] In one embodiment, the temperature in the continuous ring closure static tube reactor is 50-100°C.

[0027] In one embodiment, the temperature in the continuous ring closure static tube reactor is 75-80°C.

[0028] In one embodiment, the temperature in the continuous phase separation reactor is 50-100°C.

[0029] In one embodiment, the temperature in the continuous phase separation reactor is 75-80°C.

[0030] In one embodiment, the continuous synthesis process of the prothioconazole intermediate comprises the following steps: 1) Check the device, replace the device with high-purity nitrogen; BL-6 oil phase, formaldehyde are respectively pumped into the continuous hydrazone formation dynamic tube reactor F-1 by metering pump DP-1, metering pump DP-2 according to the flow rate of 3900-5200 kg / h, 300-400 kg / h, pass cold water to keep the temperature in the reactor at -5-5°C, obtain hydrazone, take sample, HPLC detects BL-6 residue, residue ≤0.5%, qualified; 2) The hydrazone is sheared by shearing pump DP-3 at a speed of 4000-4200 kg / h, and is pumped into the continuous ring closure static tube reactor F-2 at a flow rate of 4200-5600 kg / h; the thiocyanate aqueous solution, dilute acid aqueous solution are respectively pumped into the continuous ring closure static tube reactor F-2 by metering pump DP-4, metering pump DP-5 according to the flow rate of 860-1147 kg / h, 725-967 kg / h, pass hot water to keep the temperature in the reactor at 75-80°C, obtain BL-7 mixed phase, take sample, HPLC detects hydrazone residue, residue ≤0.5%, qualified; 3) BL-7 mixed phase into continuous phase separation device F-3, F-3 passes hot water to keep the temperature in the reactor at 75~80℃, after continuous phase separation, the light phase (brine phase) enters the receiving tank D-1, and the heavy phase (BL-7 oil phase) enters the receiving tank D-2, to obtain the final product BL-7 oil phase.

[0031] In the traditional process, in the process of synthesizing hydrazone by using batch reaction, BL-6 reacts with formaldehyde to generate by-product 1, the by-product can be subjected to subsequent reaction to generate isomer impurity 2, see the following side reaction equation: .

[0032] The application designs a continuous synthesis process, and optimizes the preparation of hydrazone from BL-6 oil phase and formaldehyde in a continuous hydrazone dynamic tubular reactor. Since the residence time is short and the reaction has little back mixing, formaldehyde and BL-6 are reacted at a suitable ratio, the yield of by-product 1 is reduced by 95% based on the original yield, the yield of impurity 2 (isomer of BL-7) is reduced by 95% due to the reduction of impurity 1, impurity 1 can continue to be subjected to subsequent reaction to generate impurity 2, isomer and BL-7 have similar physicochemical properties and can participate in subsequent reaction to generate propiconazole isomer, and it is difficult to remove, and the ring closure reaction is optimized to be carried out in a continuous ring closure static tubular reactor F-2, the residence time is short and the reaction has little back mixing, hydrazone, ammonium thiocyanate and dilute acid are reacted at a suitable ratio, and the yield of impurity 2 is reduced by 95% again, so that the final yield of impurity 2 is reduced by 90.25%.

[0033] Further, the continuous synthesis process provided by the application can continuously produce reaction products while pumping reaction raw materials, the subsequent reaction process is not affected by the products generated in the previous reaction, the degree of back mixing of the reaction liquid is very small, the reaction yield is increased by 5%, the by-products are reduced by 90.25%, and the purity reaches 99.5%.

[0034] In addition, formaldehyde and hydrogen cyanide gas are inevitably generated in the synthesis process of BL-7, which has strong toxicity and can easily cause safety accidents if leaked. In the production of BL-7, the intermediate storage is large, the reaction time is long, the safety risk is large, and the equipment requirement is high when batch production is carried out in the traditional batch reactor. At the same time, in the ring closure process, the reaction is exothermic and easy to lose control, BL-6 itself is easy to decompose toxic and harmful flammable and explosive gas, and the risk is large, so the risk is high during storage and use. The application designs a continuous synthesis process, the liquid holdup is small, the continuous feeding, continuous output and continuous post-treatment are carried out, a large amount of high-risk raw materials and intermediates do not need to be stored in the production area, the safety risk is low, and the application is green and environmentally friendly.

[0035] In another aspect of the present application, a continuous reaction device is provided, which comprises at least a continuous hydrazone-forming reaction device, a continuous ring-closing static tubular reaction device and a continuous phase separation reaction device; the continuous hydrazone-forming reaction device comprises at least a head tank G-1, a head tank G-2, a metering pump DP-1, a metering pump DP-2 and a continuous hydrazone-forming dynamic tubular reactor F-1; the continuous ring-closing static tubular reaction device comprises at least an emulsifying shear pump DP-3, a head tank G-3, a head tank G-4, a metering pump DP-4, a metering pump DP-5 and a continuous ring-closing static tubular reactor F-2; the continuous phase separation reaction device comprises at least a continuous phase separation device F-3, a receiving tank D-1 and a receiving kettle D-2; the head tank G-1 is connected with the metering pump DP-1 and then connected with the feed inlet of the continuous hydrazone-forming dynamic tubular reactor F-1, and the head tank G-2 is connected with the metering pump DP-2 and then connected with the top feed inlet of the continuous hydrazone-forming dynamic tubular reactor F-1; the discharge outlet of the continuous hydrazone-forming dynamic tubular reactor F-1 is connected with the emulsifying shear pump DP-3 and then connected with the feed inlet of the continuous ring-closing static tubular reactor F-2; the head tank G-3 is connected with the metering pump DP-4 and then connected with the top feed inlet of the continuous hydrazone-forming dynamic tubular reactor F-1, and the head tank G-4 is connected with the metering pump DP-5 and then connected with the top feed inlet of the continuous ring-closing static tubular reactor F-2; the discharge outlet of the continuous ring-closing static tubular reactor F-2 is connected with the top feed inlet of the continuous phase separation device F-3; and the two discharge outlets of the continuous phase separation device F-3 are respectively connected with the receiving tank D-1 and the receiving kettle D-2.

[0036] In the present application, the residence time of the hydrazone-forming reaction is controlled to be 2-3 minutes by using the continuous hydrazone-forming dynamic tubular reactor, the flux can reach 5000 L / h, the liquid holdup is reduced from 8 m³ to 0.1 m³, and the generation of by-products in the hydrazone-forming reaction process is inhibited by precise control of formaldehyde; the ring-closing-extraction-phase separation process is completed by using the three-stage static mixing tubular reactor, the residence time is 1-2 minutes, the flux can reach 8000 L / h, the liquid holdup is reduced from 10 m³ to 0.2 m³, the reaction temperature gradient is increased from 25℃ to 75℃ step by step, and the utilization rate of thiocyanate is 99%; the continuous phase separation system makes the oil-water separation efficiency increase by 3 times, and the purity of the crude product reaches more than 99%.

[0037] Advantages 1. The present application provides a continuous synthesis process of prothioconazole intermediate, which realizes the precise preparation of the key intermediate BL-7 through a modular continuous flow reaction system. Compared with the traditional kettle process, the continuous production cycle is shortened to 1 / 6 of the original process, the raw material utilization rate is increased by 20%, the amount of three wastes is reduced by 50%, and the risk of enrichment of toxic substances such as thiocyanic acid in the traditional process is effectively avoided, which is more suitable for industrial production.

[0038] 2、The application designs a continuous synthesis process, optimizes the preparation of hydrazone in a continuous hydrazone dynamic tubular reactor by BL-6 oil phase and formaldehyde, because of short residence time, almost no back mixing in the reaction, formaldehyde and BL-6 are reacted in a suitable ratio, the yield of by-product 1 is reduced by 95% on the basis of the original, because of the reduction of impurity 1, the yield of impurity 2 (isomer of BL-7) is reduced by 95%; cooperate to optimize the ring closure reaction in the continuous ring closure static tubular reactor F-2, short residence time, almost no back mixing in the reaction, impurity 1 and ammonium thiocyanate, dilute acid are reacted in a suitable ratio, the yield of impurity 2 is reduced by 95% again, therefore, the final yield of impurity 2 is reduced by 90.25%.

[0039] 3、The continuous synthesis process provided by the application can continuously produce reaction products while pumping reaction raw materials, the subsequent reaction process will not be affected by the products of previous reactions, the degree of back mixing of reaction liquid is very small, the reaction yield is increased by 5%, the by-products are reduced by 90.25%, and the purity reaches 99.5%.

[0040] 4、The application controls the residence time of hydrazone formation reaction in the continuous hydrazone dynamic tubular reactor to be 2-3 minutes, the flux can reach 5000L / h, the liquid holdup is reduced from the original 8m³ to 0.1m³, and the generation of by-products in the hydrazone formation reaction is inhibited by precise control of formaldehyde; the ring closure-extraction-phase separation process is completed by a three-stage static mixing tubular reactor, the reaction residence time is 1-2 minutes, the flux can reach 8000L / h, the liquid holdup is reduced from the original 10³ to 0.2m³, the reaction temperature gradient is increased from 25℃ to 75℃ step by step, and the utilization rate of thiocyanate salt is 99%; the continuous phase separation system improves the oil-water separation efficiency by 3 times, and the purity of the crude product reaches more than 99%.

[0041] 5、The continuous synthesis process and device provided by the application are simple to operate, have less equipment usage, high site utilization rate, low labor cost, low equipment cost, and are easy to realize large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 The structure schematic view of the continuous synthesis device of the propiconazole intermediate provided for example 1, in the figure, the high tank G-1, the high tank G-2, the metering pump DP-1, the metering pump DP-2, the continuous hydrazone dynamic tubular reactor F-1, the emulsifying shear pump DP-3, the high tank G-3, the high tank G-4, the metering pump DP-4, the metering pump DP-5 and the continuous ring closure static tubular reactor F-2, the continuous phase separation device F-3, the receiving tank D-1, and the receiving kettle D-2. DETAILED DESCRIPTION

[0043] Example 1 Embodiment 1 of the present application provides a continuous synthesis process of a prothioconazole intermediate, comprising the following steps: 1) checking device, high-purity nitrogen replacement device; BL-6 oil phase, formaldehyde are respectively pumped into a continuous hydrazone dynamic tubular reactor F-1 through a metering pump DP-1 and a metering pump DP-2 according to a flow rate of 3900 kg / h and 300 kg / h, cold water is passed to keep the temperature in the reactor at 0±2℃, a hydrazone is obtained, sampling is performed, HPLC detection is performed on the residual BL-6, and the residual BL-6 is less than or equal to 0.5%, which is qualified; 2) the hydrazone is sheared through a shearing pump DP-3 according to a speed of 4200 kg / h, is pumped into a continuous ring-closing static tubular reactor F-2 according to a flow rate of 4200 kg / h, a thiocyanate aqueous solution and a dilute acid aqueous solution are respectively pumped into the continuous ring-closing static tubular reactor F-2 through a metering pump DP-4 and a metering pump DP-5 according to flow rates of 860 kg / h and 725 kg / h, hot water is passed to keep the temperature in the reactor at 78±2℃, a BL-7 mixed phase is obtained, sampling is performed, HPLC detection is performed on the residual hydrazone, and the residual hydrazone is less than or equal to 0.5%, which is qualified; 3) the BL-7 mixed phase enters a continuous phase separation device F-3, the F-3 is passed through hot water to keep the temperature in the reactor at 78±2℃, continuous phase separation is performed, a light phase (a salt water phase) enters a receiving tank D-1, and a heavy phase (a BL-7 oil phase) enters a receiving kettle D-2, a final product BL-7 oil phase is obtained, sampling is performed, HPLC detection is performed on the BL-7, the content of the BL-7 is 99.8%, the content of impurity 1 is 0.1%, the content of impurity 2 is 0.03%, and the total yield is 97%.

[0044] The BL-6 oil phase comprises BL-6 and a solvent, the weight ratio of the BL-6 to the solvent is 1:3, and the solvent is dichloroethane.

[0045] The formaldehyde is a 35wt% formaldehyde aqueous solution.

[0046] The weight ratio of thiocyanate to water in the thiocyanate aqueous solution is 1:2, and the thiocyanate is ammonium thiocyanate.

[0047] The weight ratio of acid to water in the dilute acid aqueous solution is 1:2, and the acid is sulfuric acid.

[0048] Reference can be made to Figure 1In another aspect, Embodiment 1 of the present invention provides a continuous reaction apparatus, including a continuous hydrazone formation reaction apparatus, a continuous closed-loop static tubular reaction apparatus, and a continuous phase-separation reaction apparatus; the continuous hydrazone formation reaction apparatus includes a high-level tank G-1, a high-level tank G-2, metering pumps DP-1 and DP-2, and a continuous hydrazone formation dynamic tubular reactor F-1; the continuous closed-loop static tubular reaction apparatus includes at least an emulsification shear pump DP-3, a high-level tank G-3, a high-level tank G-4, metering pumps DP-4 and DP-5, and a continuous closed-loop static tubular reactor F-2; the continuous phase-separation reaction apparatus includes at least a continuous phase-separation apparatus F-3, a receiving tank D-1, and a receiving vessel D-2; the high-level tank G-1 is connected to the metering pump DP-1 and then to the continuous hydrazone formation dynamic tubular reactor F-1. The feed inlet of the continuous hydrazone dynamic tubular reactor F-1 is connected to the high-level tank G-2, which is connected to the metering pump DP-2 and then to the top feed inlet of the continuous hydrazone dynamic tubular reactor F-1. The discharge outlet of the continuous hydrazone dynamic tubular reactor F-1 is connected to the emulsification shear pump DP-3 and then to the feed inlet of the continuous closed-loop static tubular reactor F-2. The high-level tank G-3 is connected to the metering pump DP-4 and then to the top feed inlet of the continuous hydrazone dynamic tubular reactor F-1. The high-level tank G-4 is connected to the metering pump DP-5 and then to the top feed inlet of the continuous closed-loop static tubular reactor F-2. The discharge outlet of the continuous closed-loop static tubular reactor F-2 is connected to the top feed inlet of the continuous phase separation device F-3. The two discharge outlets of the continuous phase separation device F-3 are respectively connected to the receiving tank D-1 and the receiving vessel D-2.

[0049] Example 2 Example 2 of the present invention provides a continuous synthesis process and apparatus for a prothioconazole intermediate. The specific implementation method is the same as that of Example 1, except that in step 1), chilled water is circulated to maintain the temperature inside the reactor at 20±2℃; the final product BL-7 oil phase is sampled and analyzed by HPLC. The normalized content of BL-7 is 97.8%, the content of impurity 1 is 1.38%, the content of impurity 2 is 0.82%, and the total yield is 96%.

[0050] Example 3 Embodiment 3 of the present application provides a continuous synthesis process and device of a prothioconazole intermediate, the specific implementation of which is the same as that of Embodiment 1, except that in step 1), the BL-6 oil phase, formaldehyde are respectively pumped into the continuous hydrazone dynamic tubular reactor F-1 by the metering pump DP-1 and the metering pump DP-2 at a flow rate of 5200 kg / h and 400 kg / h; the hydrazone is sheared by the shearing pump DP-3 at a speed of 4200 kg / h and pumped into the continuous ring-closing static tubular reactor F-2 at a flow rate of 5600 kg / h; the thiocyanate aqueous solution and the acid are respectively pumped into the continuous ring-closing static tubular reactor F-2 by the metering pump DP-4 and the metering pump DP-5 at a flow rate of 1147 kg / h and 967 kg / h; the final product BL-7 oil phase is sampled, and the HPLC detection shows that the BL-7 normalized content is 97.1%, the impurity 1 content is 2.62%, the impurity 2 content is 0.28%, and the total yield is 95%.

[0051] Comparative Example 1 Comparative Example 1 of the present application provides a batch kettle synthesis process of a prothioconazole intermediate, which comprises the following steps: 1) The 8000L reactor is replaced by nitrogen, 6800kg of BL-6 oil phase is added, the temperature is controlled at 8±2℃, 560kg of formaldehyde is added dropwise, the dropwise addition is completed in 2 hours, and the dropwise addition is completed for 2 hours, to obtain a hydrazone, sampling, HPLC detection of BL-6 residue, residue≤1.5%, qualified; 2) Start adding 1800g of ammonium thiocyanate aqueous solution, control the temperature at 12±2℃, complete the dropwise addition in 3 hours, keep the temperature for 1 hour after the dropwise addition is completed, control the reaction temperature at 28±2℃, continue to add the dilute acid aqueous solution, after the dropwise addition is completed, continue to stir for 5 hours, sampling, HPLC detection of hydrazone residue, residue≤2.5%, qualified, HPLC detection shows that the BL-7 normalized content is 96.8%, the impurity 1 content is 2.12%, the impurity 2 content is 0.18%, and the total yield is 93%.

[0052] The BL-6 oil phase comprises BL-6 and a solvent, and the weight ratio of the BL-6 to the solvent is 1:3, and the solvent is dichloroethane.

[0053] The formaldehyde is a 35wt% formaldehyde aqueous solution.

[0054] The weight ratio of the thiocyanate to water in the thiocyanate aqueous solution is 1:2, and the thiocyanate is ammonium thiocyanate.

[0055] The weight ratio of the acid to water in the dilute acid aqueous solution is 1:2, and the acid is sulfuric acid.

[0056] Comparative Example 2 Comparative Example 2 of the present application provides a batch kettle synthesis process of a prothioconazole intermediate, which comprises the following steps: 1) 8000L reactor nitrogen replacement, the BL-6 oil phase 6800kg is added, the temperature is controlled to 8±2 ℃, 560kg of formaldehyde is added dropwise, 1 hour dropwise is completed, after the dropwise addition is completed, 2 hours are preserved, a hydrazone is obtained, sampling, HPLC detects that the BL-6 residue is less than or equal to 1.5%, and it is qualified; 2) 1800g of an aqueous ammonium thiocyanate solution is started to be added dropwise, the temperature is controlled to 12±2 ℃, 3 hours dropwise are completed, after the dropwise addition is completed, 1 hour is preserved, the reaction temperature is controlled to 28±2 ℃, the dilute acid aqueous solution is continuously added dropwise, after the dropwise addition is completed, the stirring is continuously carried out for 5 hours after the preservation, sampling, HPLC detects that the hydrazone residue is less than or equal to 2.5%, and it is qualified, HPLC detects that the BL-7 normalized content is 94.8%, the impurity 1 content is 6.1%, the impurity 2 content is 0.7%, and the total yield is 92%.

[0057] The BL-6 oil phase includes BL-6 and a solvent, and the weight ratio of the BL-6 to the solvent is 1:3, and the solvent is dichloroethane.

[0058] The formaldehyde is a 35wt% formaldehyde aqueous solution.

[0059] The weight ratio of the thiocyanate to water in the thiocyanate aqueous solution is 1:2, and the thiocyanate is ammonium thiocyanate.

[0060] The weight ratio of the acid to water in the dilute acid aqueous solution is 1:2, and the acid is sulfuric acid.

[0061] Comparative Example 3 The comparative example 3 of the present application provides a batch kettle type synthesis process of a prothioconazole intermediate, including the following steps: 1) 8000L reactor nitrogen replacement, the BL-6 oil phase 6800kg is added, the temperature is controlled to 8±2 ℃, 560kg of formaldehyde is added dropwise, 2 hours dropwise are completed, after the dropwise addition is completed, 2 hours are preserved, a hydrazone is obtained, sampling, HPLC detects that the BL-6 residue is less than or equal to 1.5%, and it is qualified; 2) 1800g of an aqueous ammonium thiocyanate solution is started to be added dropwise, the temperature is controlled to 12±2 ℃, 1 hour dropwise is completed, after the dropwise addition is completed, 1 hour is preserved, the reaction temperature is controlled to 28±2 ℃, the dilute acid is continuously added dropwise, after the dropwise addition is completed, the stirring is continuously carried out for 5 hours after the preservation, sampling, HPLC detects that the hydrazone residue is less than or equal to 2.5%, and it is qualified, HPLC detects that the BL-7 normalized content is 92.3%, the impurity 1 content is 1.5%, the impurity 2 content is 6.2%, and the total yield is 92%.

[0062] The BL-6 oil phase includes BL-6 and a solvent, and the weight ratio of the BL-6 to the solvent is 1:3, and the solvent is dichloroethane.

[0063] The formaldehyde is a 35wt% formaldehyde aqueous solution.

[0064] The weight ratio of thiocyanate and water in the aqueous thiocyanate solution is 1 :2, and the thiocyanate is ammonium thiocyanate.

[0065] The weight ratio of acid and water in the dilute aqueous acid solution is 1 :2, and the acid is sulfuric acid.

Claims

1. A continuous synthesis process for a prothioconazole intermediate, characterized in that, At least the following steps are included: BL-6 oil phase and formaldehyde are used to synthesize hydrazone in a continuous hydrazone synthesis reactor; hydrazone is used with thiocyanate aqueous solution and dilute acid aqueous solution in a continuous closed-loop static tubular reactor to synthesize BL-7 mixed phase; BL-7 mixed phase is separated in a continuous phase separation reactor to obtain BL-7 oil phase and brine phase, and BL-7 oil phase contains prothioconazole intermediate BL-7.

2. The continuous synthesis process of the prothioconazole intermediate according to claim 1, characterized in that, The BL-6 oil phase comprises BL-6 and a solvent, wherein the weight ratio of BL-6 to the solvent is 1:(1~20).

3. The continuous synthesis process of the prothioconazole intermediate according to claim 2, characterized in that, The solvent is selected from one or a combination of several of toluene, xylene, dichloroethane, trichloroethane, dichloromethane, ethyl acetate, or cyclohexane.

4. The continuous synthesis process of the prothioconazole intermediate according to claim 1, characterized in that, The formaldehyde is selected from one or a combination of several of the following: gaseous formaldehyde, 5-40 wt% formaldehyde aqueous solution, or paraformaldehyde.

5. The continuous synthesis process of the prothioconazole intermediate according to claim 1, characterized in that, The weight ratio of thiocyanate to water in the thiocyanate aqueous solution is 1:(1~5).

6. The continuous synthesis process of the prothioconazole intermediate according to claim 5, characterized in that, The thiocyanate is selected from one or a combination of several of potassium thiocyanate, sodium thiocyanate, ammonium thiocyanate, mercuric thiocyanate, or lead thiocyanate.

7. The continuous synthesis process of the prothioconazole intermediate according to claim 2, characterized in that, The molar ratio of BL-6 to formaldehyde is 1:(1.0~2).

8. The continuous synthesis process of the prothioconazole intermediate according to claim 5, characterized in that, The molar ratio of BL-6 to thiocyanate is 1:(1~3).

9. The continuous synthesis process of the prothioconazole intermediate according to claim 1, characterized in that, The temperature inside the continuous hydrazone formation reactor is -25~25℃.

10. A continuous synthesis apparatus for a prothioconazole intermediate, used in the continuous synthesis process of the prothioconazole intermediate according to any one of claims 1-9, characterized in that, The reactor comprises at least a continuous hydrazone formation reactor, a continuous closed-loop static tubular reactor, and a continuous phase-separation reactor. The continuous hydrazone formation reactor includes at least a high-level tank G-1, a high-level tank G-2, metering pumps DP-1 and DP-2, and a continuous hydrazone formation dynamic tubular reactor F-1. The continuous closed-loop static tubular reactor includes at least an emulsifying shear pump DP-3, a high-level tank G-3, a high-level tank G-4, metering pumps DP-4 and DP-5, and a continuous closed-loop static tubular reactor F-2. The continuous phase-separation reactor includes at least a continuous phase-separation device F-3, a receiving tank D-1, and a receiving vessel D-2. The high-level tank G-1 is connected to metering pump DP-1 and then to the inlet of the continuous hydrazone formation dynamic tubular reactor F-1. Tank G-2 is connected to metering pump DP-2 and then to the top inlet of the continuous hydrazone formation dynamic tubular reactor F-1; the outlet of the continuous hydrazone formation dynamic tubular reactor F-1 is connected to emulsification shear pump DP-3 and then to the inlet of the continuous closed-loop static tubular reactor F-2; the high-level tank G-3 is connected to metering pump DP-4 and then to the top inlet of the continuous hydrazone formation dynamic tubular reactor F-1; the high-level tank G-4 is connected to metering pump DP-5 and then to the top inlet of the continuous closed-loop static tubular reactor F-2; the outlet of the continuous closed-loop static tubular reactor F-2 is connected to the top inlet of the continuous phase separation device F-3; the two outlets of the continuous phase separation device F-3 are respectively connected to receiving tank D-1 and receiving vessel D-2.

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